Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival.
BACKGROUND
Constitutive activation of signal transducer and activator of transcription 3 (Stat3) signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer.


RESULTS
We found that elevated Stat3 phosphorylation in 19 of 100 (19%) bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F) and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC). The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin) and a cell cycle regulating gene (cyclin D1) was associated with the cell growth inhibition and apoptosis.


CONCLUSIONS
These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.
Chen
Chun-Liang
CL
Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. Chun-Liang.Chen@nationwidechildrens.org
Cen
Ling
L
Kohout
Jennifer
J
Hutzen
Brian
B
Chan
Christina
C
Hsieh
Fu-Chuan
FC
Loy
Abbey
A
Huang
Victor
V
Cheng
Gong
G
Lin
Jiayuh
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011083:Polycyclic Compounds / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
D011083:Polycyclic Compounds; C500947:STA-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020169:Caspases